Abstract Electronic cigarettes (e-cigs), were introduced to the U.S. market only 10 years ago and are markedly different from traditional tobacco-based cigarettes. Whereas traditional cigarettes are smoked through combustion, e-cigarettes are ?vaped? (i.e., heated), and the resultant aerosols contain a far smaller number of potentially toxic chemicals, such as nicotine and flavorings (e.g., cinnamaldehyde and diacetyl), as well as byproducts (e.g., acrolein and formaldehyde) caused by the potential overheating of these agents, propylene glycol, and glycerin. Thus, although e-cigarettes are widely believed and marketed as a safer alternative to cigarette smoking, the actual danger posed by its use remains largely unexplored. As the use of e-cigs steadily rises, the number of health effects studies is still relatively small and have focused on short term effects. These studies, however, have demonstrated adverse pulmonary and cardiovascular effects in human subjects and test animals. To date, some long term human health effects studies have investigated e- cigarettes as cessation devices, but such epidemiology studies are confounded by the `poly-use' of e- cigarettes and previous (and possibly concurrent) traditional tobacco cigarettes. Therefore, the studies proposed in this grant application will avoid this confounding and utilize established animal models, previously used in long-term tobacco studies, to investigate the adverse cardiopulmonary effects of e-cigarettes after chronic inhalation exposures. In particular, the proposed experiments are designed to discern: 1) the toxicity of the e-liquid aerosols themselves, with and without added flavorings, generated at different voltages (i.e. heating coil temperatures); and 2) the contribution of innate modifying factors, such as sex, glutathione biomarkers and pathways, and genetics, to e-cigarette toxicity. We will test the overall hypothesis that chronic exposure to e-cigarette aerosols produces adverse cardiopulmonary effects and that these effects are modified by innate factors, such as genetic heterogeneity and sex (i.e., gender), and exogenous factors, such as flavorings and e-cigarette coil temperature.